Aryl-2-amino-imidazolines are well-known in the art. Compounds such as moxonidine, para-aminoclonidine, brimonidine and tramazoline are but a few of the compounds which contain this basic structural feature that have also found use as therapeutic agents. For a review of structure activity relationships of this type of compound in relation to adrenergic receptors see R. Ruffolo, Jr. (ed.) in .alpha.-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, Prog. Basic Clin. Pharmacol. (Basel, Karger), 8 pp. 75-114 (1991). ##STR2##
A compound of similar structure is moxonidine. However, moxonidine has been identified pharmacologically as a selective imidazoline receptor agonist, with utility as a centrally-acting antihypertensive agent. The pharmacological investigation of imidazoline agents independent of adrenoceptors started in the mid-1980's. Two major subtypes, tentatively designated I.sub.1 and I.sub.2, are recognized. I.sub.1 sites are labeled with nanomolar affinity by clonidine analogs whereas I.sub.2 sites have micromolar affinity for clonidine and are usually labeled by tritiated idazoxan. The `I` designation (for imidazoline) has been intended to encompass not only imidazolines, imidazoles, and imidazolidines, but also such related structures as guanidines and oxazolines, all of which are potential ligands at these sites. A recent review of imidazoline-preferring receptors has been published by M. C. Michel and P. Ernsberger in TiPS, 13, pp. 369-379 (Oct. 1992). ##STR3##
Studies to identify the mechanism of the selective antihypertensive action of moxonidine have shown that the effect is mediated mainly by 1.sub.1 -imidazoline receptors in the rostral ventrolateral medulla. [Haxhiu, M. A. et al, J. Cardiovasc. Pharmacol. 24 (suppl.1) pp. S1-S8 (1994)]. Similar studies of related compounds have identified rilmenidine as a hypotensive drug that is more selective for imidazoline receptors than for classical .alpha..sub.2 adrenoceptors [Bousquet, P., et al., Am. J. Hypertens. 5 pp 47S-50S, 1992]. The rilmenidine structure substitutes an oxazolidine ring for imidazoline. Such heterocyclic ring substitutions are noted in the Ruffolo monograph on page 99 to reduce or abolish activity at .alpha..sub.2 receptors. A study published by Harron, D. W. (Am. J. Hypertens., 5(4, Pt. 2) pp. 91S-98S (April 1992) reported that in experimental studies, "rilmenidine differs from clonidine in that it is more selective for imidazoline receptors than for .alpha..sub.2 -adrenoceptors; at equihypotensive doses, rilmenidine causes less bradycardia and reduction in cardiac output, less sedation, and little or no antinociceptive action compared to clonidine". ##STR4##
A few aryl-2-amino-imidazole derivatives are known in the pharmaceutical arts: Jen, et al in J. Med. Chem., 18(1). 90-99 (1975) made and tested a clonidine analog, among a few other related structures for antihypertensive and gastric antisecretory activity. U.S. Pat. No. 3,459,763 (to Gruenfeld) which discloses a variety of substituted imidazole compounds, the two classes of compounds disclosed are regioisomers of the general structures: phenyl-2-amino-imidazole and N-1-phenyl-2-amino-imidazole. These structures were disclosed as having cardiovascular and anti-inflammatory activities.
In addition, several drugs are known which substitute a methylene group for the bridging amino group in the imidazoline series, compounds such as oxymetazoline, naphazoline and tolazoline are examples. The Ruffolo review indicates at page 95 that "replacement of the nitrogen bridge of clonidine with a methylene bridge has little effect on .alpha..sub.2 adrenoceptor activity . . . " and elsewhere on p. 95 that the "replacement of the nitrogen atom in clonidine-like imidazolines with either carbon or sulfur produces only a small reduction in .alpha..sub.2 adrenoceptor activity".
The background of the division of adrenergic receptor system into differing categories and subtypes can be briefly described as follows. Historically, adrenoceptors were first divided in .alpha. and .beta. types by Ahlquist in 1948. This division was based on pharmacological characteristics. Later, .beta.-adrenoceptors were subdivided into .beta..sub.1 and .beta..sub.2 subtypes, again based on a pharmacological definition by comparison of the relative potencies of 12 agonists. The .alpha.-adrenoceptors were also subdivided into .alpha..sub.1 and .alpha..sub.2 subtypes, initially based on a presumed localization of .alpha..sub.1 receptors postsynaptically and .alpha..sub.2 presynaptically. Now, however, this physiologic division is no longer used and it is generally accepted that the most useful way to subdivide the .alpha.-adrenoceptors is based on pharmacology using affinities for the antagonists yohimbine and prazosin. At .alpha..sub.1 receptors, prazosin is more potent that yohimbine, whereas the .alpha..sub.2 receptors, yohimbine is more potent than prazosin. Bylund, et al. first suggested in 1981 that there possibly existed subtypes of the .alpha..sub.2 -adrenoceptors on the basis of radioligand binding studies. This initial work was done with various tissues taken from various species. While receptor heterogeneity among species is considered to be important, the term `subtype` is usually reserved by pharmacologists for heterogeneity which can be demonstrated within the same species and ideally within a single tissue. Bylund and coworkers have later demonstrated that some regions of the human and rat brain contain two populations of .alpha..sub.2 -adrenoceptors sites which differ in their affinity for prazosin by 30- to 40-fold.
This finding supports the division of the .alpha..sub.2 receptor into A and B subtypes. More recently there have been reports of a third alpha subtype receptor called 2C.
Some examples of alpha.sub.2 (.alpha..sub.2) adrenergic receptor agonists well known in the art are: ##STR5##
Clonidine is clinically useful as a hypotensive agent, and has been studied as a nasal decongestant and as an ocular hypotensive agent and as an anesthetic adjunct. The mechanism of action of clonidine has been described as a centrally acting .alpha..sub.2 adrenergic partial agonist, however, clonidine also has hypotensive cardiovascular effects. It was reported that clonidine binds to both .alpha..sub.2 and imidazoline receptors and that the binding to the imidazoline receptors mediates the blood pressure lowering side effects of clonidine. [See e.g. Codd, E. E., et al. Life Sci., 56 (2) p. 63-74 (Dec. 2, 1994) and Ernsberger, P., et al., Cardiovasc. Drugs Ther., 8 (Suppl. 1) pp. 27-41 (March 1994)] Brimonodine (UK 14,304) is a newer .alpha..sub.2 adrenergic agent which possesses superior therapeutic action as an ocular hypotensive, and has been tested in other .alpha.2 agonist responsive conditions. Brimonidine, as is shown by the data in table I at Example 4 also shows significant imidazoline receptor binding affinity. Other activities inferred by I-receptor studies are stimulation of insulin release from pancreatic .beta.-cells via coupling to ATP-sensitive K+ channels and inhibition of sodium reabsorption in the tubules of the kidneys. It has now been suggested by the present inventors that the imidazoline receptor is a nonfunctional binding site. [See Munk, S. A., et al, J. Med. Chem. 39 (6) 1193-1195(1996).]
A few compounds which have been reported to be a2A selective are dexmedetomidine and oxymetazoline. ##STR6##
The identification of subtypes of the .alpha..sub.2 receptor has progressed faster than complete pharmacological and physiological characterization of them. Nevertheless, .alpha..sub.2A receptors have been identified in the ciliary body of the eye, and so are postulated to have a controlling mechanism in ocular hypertension and symptomatology of glaucoma (see Sin, Y. et al., J. Ocul. Pharmacol. 10(1) pp. 359-69 (1994). Alpha .sub.2A receptors have also been studied in pain perception, or alternatively, pain alleviation (see Millan, M. J., Eur. J. Pharmacol., 215(2-3) pp. 355-6 (1992).
A selective or subtype selective agonist as the term is used in this invention indicates a compound that binds to, and activates, a specific receptor subtype in preference to other receptors of related but different subtype(s). For example, a compound that binds to and activates the .alpha..sub.2A subtype receptor in preference to the .alpha..sub.2B or .alpha..sub.2C subtype receptors is an .alpha..sub.2A selective agonist. Activation means that the receptor is induced to initiate a biochemical event that is controlled or operated by that particular receptor. Activation can further be thought of in terms of a signal transduction process which mediates the signal triggered by receptor activation to intracellular effector structures.
From this summary of the state of the art it is apparent that compounds which are selective .alpha..sub.2 agonists possess valuable therapeutic utility for treating glaucoma and pain, and for producing sedation.